Most studies point to the mesocorticolimbic dopamine (DA) system as the necessary neurobiological endpoint when describing cocaine's rewarding properties; however, this system does not operate in isolation, and input from other structures may play a significant role in cocaine reward. One area that has received little attention as a potential modulator of cocaine-induced activity is the medial preoptic area of the hypothalamus (MPOA). The MPOA is involved in the regulation of two naturally rewarding behaviors (maternal and sexual behaviors), is sexually dimorphic, and interacts with areas in the mesocorticolimbic system. As such, the MPOA is a logical candidate for a neuroanatomical locus modulating cocaine-induced activity, yet surprisingly little is known about the role of this structure in the context of drug abuse. Here, we focus on preclinical animal models of cocaine reward, hypothesizing that the MPOA modulates cocaine-induced activity in the mesocorticolimbic system and resulting behavioral expression of reward, including sex differences. The proposed studies will answer the following questions: (1) Does the MPOA modulate cocaine-induced neuronal and dopamine activity in the mesocorticolimbic system? (2) Does the MPOA modulate cocaine reward? (3) Do cells in the MPOA containing gonadal-hormone receptors interact with the mesocorticolimbic system? (4) Do gonadal hormones act via the MPOA to modulate cocaine-induced neuronal and dopamine activity in the mesocorticolimbic system? (5) Do gonadal hormones act via the MPOA to modulate cocaine reward? Using neuroanatomical, neurochemical, and behavioral assays, the proposed work will examine whether the MPOA may serve as an extension of the reward pathway in modulating cocaine-induced activity. The findings from these studies will yield a greater understanding of the neurochemical and neuroendocrine substrates regulating cocaine reward. A greater understanding of the neurochemical and neuroendocrine regulation of cocaine reward will facilitate the development of treatment for drug addiction, when hormonal factors may be especially important. PUBLIC HEALTH RELEVANCE: According to the National Survey on Drug Use and Health (NSDUH), in 2009 there were 1.6 million current cocaine users aged 12 or older, comprising 0.7 percent of the nation's population. This is a dangerous epidemic because cocaine use can produce addiction and other adverse health consequences. As evidence of the addictive consequences of cocaine use, according to the NSDUH, nearly 1.1 million Americans met the DSM-IV criteria for dependence or abuse of cocaine in 2009. Additional data also indicate that 448,481 of the total 1,449,154 visits to emergency rooms for drug abuse involved cocaine, highlighting the adverse health consequences of cocaine use. Studies presented in this proposal will examine a region of the brain that has received little attention as a potential modulator of cocaine activity. This brain region is important for the integration of endocrine stimulation into the nervous system. Since gonadal hormones modulate rewarding and gender-sensitive responses to cocaine, the preclinical findings generated upon completion of the planned experiments will help us better understand the neurochemical, neuroendocrine, and gender-relevant substrates regulating cocaine abuse. The successful completion of the proposed aims will facilitate the development of prevention and treatment strategies for addiction, especially if these strategies involve an endocrine component. Furthermore, because pharmacological and behavioral treatments affect men and women differently, then a better understanding of how hormones impact cocaine-induced brain activity, while developing future treatment, should optimize the effectiveness of those treatment strategies.